Researchers find first gene that increases risk of Crohn's disease

A team of researchers, from the University of Chicago, the University of Michigan, and others, has identified the first genetic abnormality that increases susceptibility to Crohn's disease.

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In the 31 May, 2001, issue of Nature (published 21 May on the journal's website) the researchers report that mutations of Nod2 significantly increase the risk of Crohn's disease. This gene is involved in the immune system's initial response to bacterial infection.

A companion paper by French scientists in the same journal confirms the link in a different group of patients.

Nod2 encodes a protein that helps the innate immune system recognize and respond to the presence of lipopolysaccharides, a component of the outer membrane of certain types of bacteria.

The researchers found that the mutated forms of Nod2 were truncated; about 3% of the protein was missing. This altered version of the protein was much less effective in recognizing the bacterial components and triggering the release of chemical signals that launch an immune response.

Mutated NOD2 inefficient in triggering immune system in response to bacteria.

Nature

How a less responsive immune system triggers inflammation is unclear.

The authors theorize that this early deficit in sensing bacteria by the innate immune system might result in an exaggerated inflammatory response subsequently by the adaptive immune system. The latter reacts more slowly, but produces very targeted weapons against invaders and retains a lasting 'memory' of prior infections.

About 8% of Caucasians have one abnormal version of Nod2. About 15% of Crohn's patients have the altered form of the gene.

Having one copy doubles the risk of Crohn's disease. Having two copies increases the risk 15- to 20-fold.

The authors comment that this is just the first of several genes that increase risk for Crohn's disease.

Judy Cho, Assistant Professor of Medicine and a researcher in the Martin Boyer Laboratories at the University of Chicago, said, "By providing clues to disease pathways and directing us to related proteins, the identification of Nod2 mutations may accelerate the process of finding subsequent Crohn's disease-associated mutations.

"If we can figure out how these genes interact with each other and the environment, we may someday be able to develop better treatments, as well as determine which treatments will work best in which patients.

"We may be able to define which strains of intestinal bacteria interact with Nod2 to increase or decrease intestinal inflammation," she concluded.